Continued support of the Great Lakes New England (GLNE) Clinical Validation Center (CVC) of the Early Detection Research Network (EDRN) via the U01 mechanism is requested. The GLNE CVC is a highly collaborative, multi-institutional consortium designed to develop, implement and analyze trials for the validation of biomarkers for the early detection of colorectal adenocarcinoma and other GI malignancies. Over the last 15 years, the GLNE has: 1. developed a high quality repository of samples collected from human subjects with colorectal, lower esophageal neoplasias, pancreatic neoplasms and controls; 2. collaborated with 9 biomarker developmental laboratories, 4 biomarker reference laboratories, the EDRN DMCC, and 9 industrial partners publishing 36 collaborative manuscripts; 3. Performed phase I validation trials of 26 biomarkers for the early detection of colorectal adenocarcinoma; 4. Initiated and recruited 5,154 participants to a Network-wide cross sectional validation trial of biomarkers for the early detection of colorectal cancer. The GLNE proposes to 1. Complete an ongoing prospective Phase 2 validation trial of vimentin methylation, serum galectin-3 ligand, BCAT1/IKZF1 methylation in plasma, fecal immunochemical tests (FIT), Exact Sciences stool DNA panel, or any future individual biomarker individually and as a panel for the early detection of colorectal neoplasia using colonoscopy as the gold standard; 2. To perform phase 1 validation trials (training and test set designs) of promising biomarkers discovered by EDRN Biomarker Validation Laboratories, external academic collaborating institutions, and collaborating EDRN industrial partners for the early detection of colorectal cancer, high grade colorectal dysplasia, and screen relevant colorectal neoplasms; 3. Assess the frequency of missed or occult colonic and upper gastrointestinal neoplasia in patients with initially normal colonoscopies and persistently positive stool DNA testing; and 4. Continue to expand and renew the archive of appropriately preserved stool, serum, plasma, urine, tissue and DNA biospecimens to be used by EDRN investigators for future validation and biomarker discovery research. These aims will be addressed by a multi-institutional consortium of university and community GI practices recruiting human subjects undergoing screening colonoscopy under a PRoBE compliant protocol. The data will be managed and analyzed by the EDRN data management and coordinating center.